Small for gestational age (SGA) is defined as a birth weight less than 2 standard deviations (SD) below the 3rd percentile. Between 2.5% to 10% of each population meet the criteria for SGA. This nomenclature is confusing and has therefore been contested [Laron Z., Ped. Endocrinol. Rev. 2009, 7(2):2], as small means also short.
Fetal growth restriction may occur early or late during fetal development. Infants who demonstrate reduced fetal growth early in gestation constitute approximately 20% of all SGA infants. They are symmetrically growth retarded: head circumference, weight, and length are proportionately affected to equivalent degrees. The Ponderal Index (weight divided by length cubed) or other body proportion ratios (head circumference to weight or length, femur length to abdominal circumference, head circumference to abdominal circumference) are used to detect symmetrical growth restriction during the fetal period [Verkauskiene R. et al., Eur J Endocrinol 2007; 157:606-12]. In addition to inherent genetic growth constraints, chromosomal disorders, congenital syndromes, IGF-1 (Insulin-Like Growth Factor-1) deficiency and early congenital viral infections, reduce the intrauterine growth rate at an early stage of development.
Intrauterine growth restriction may lead to infants being born SGA. SGA is associated with increased perinatal mortality and morbidity and postnatal growth failure [De Bie H. M. A. et al., Horm. Res. Paediatr. 2010, 73:6-14]. Fetal growth restriction is also associated with neuro-developmental pathology and contributes to late onset disorders such as cardiovascular disease, insulin resistance, and non insulin dependent diabetes [De Bie H. M. A. et al., Horm. Res. Paediatr. 2010, 73:6-14]. In addition, SGA children have decreased levels of intelligence and cognition, although the effects may be subtle [De Bie H. M. A. et al., Horm. Res. Paediatr. 2010, 73:6-14]. In four recent cohort studies, data was collected prospectively on pregnancy, birth and late developmental outcomes of large numbers of SGA term born infants. Strauss [Strauss R. S., J.A.M.A. 2000, 283:625-632] identified 1064 of 14189 term infants as SGA infants. Follow up at 5, 10, 16 and 26 years was 93%, 80%, 72% and 53% respectively. At follow-up (5-16 years), those born SGA demonstrated small but significant deficits in academic achievement. Teachers were less likely to rate them in the top 15% of the class at 16 years (13% vs 20%, P<0.01) and more likely to recommend special education (4.9% vs 2.3%, P<0.01) compared with those born at normal birth weight. At the age of 26 years, adults born SGA didn't demonstrate any difference in years of education, employment, marital status, or satisfaction with life. However, adults born SGA were less likely to have professional or managerial jobs (8.7% vs 16.4% P<0.01) and had significantly lower incomes. Larroque et al [Larroque B., Pediatrics 2001, 108:111-115] identified 218 SGA infants and 279 appropriate for gestational age (AGA) infants in a French cohort of 20,000 births born between 1971-1985. Late entry into secondary school was more frequent for SGA then AGA children. A significantly higher proportion of SGA adolescent failed to take or pass the baccalaureate examination than AGA adolescent. O'Keeffe et al [O'Keeffe M. J., Pediatrics 2003, 112:301-307] studied Australian children that were SGA or AGA infants and their mothers. Learning problems were present in 32% of the SGA group compared to 18% in the AGA group (p<0.001). The SGA group also performed inferiorly on the administered reading test, 22% vs 14% (p<0.001) in the AGA group. Lundgren et al. [Lundgren E. M. et al., Horm. Res. 2003, 59 (Suppl. 1):139-141] analyzed data from the Swedish Conscript Register. Intellectual and psychological performance was assessed. Low birth weight, short birth length, small head circumference and preterm birth increased the risk of subnormal intellectual and psychological performance. Among SGA the most important predictor was absence of catch-up growth.
Increasing evidence has shown that children born SGA, especially those born very small (short and underweight) suffer subsequently from neuro-developmental retardation and abnormalities [De Bie H. M. A. et al., Horm. Res. Paediatr. 2010, 73:6-14] and learning difficulties when reaching school age and even at later age [Tuvemo T. and Lundgren E. M., In: Kiess W, Chernausek S D, Hokken-Koelega A C S (eds.) Small for Gestational Age. Causes and Consequences. Basel, Karger, 2009:134-147]. A positive correlation between head circumference (HC), estimated brain weigh, and neurologic development during the first years has been shown [Sommerfelt K. et al., Arch. Dis. Child. 2000, 83:25-30; Gale C. R. et al., Brain 2004, 127:321-329; Gross S. J. et al., Am. J. Dis. Child. 1978, 132:753-756].
Congenital GH deficiency or GH insensitivity (Laron syndrome) result not only in reduced birth length, but also in a small HC [Laron Z., J. Clin. Endocrinol. Metab. 2004, 89:1031-1044; Laron Z. et al., In: Castells S, Wisniewski K E (eds). Growth Hormone Treatment in Down's Syndrome. John Wiley & Sons Ltd., 1993:151-161; Laron Z., Chapter 14. In: Rubin R T, Pfaff D, Eds. Hormone/behavior relations of clinical importance: Endocrine systems interacting with brain and behavior. Elsevier-Academic Press, New York, 2009, pp. 373-394] denoting retarded brain growth.
GH receptors (GH-R) and IGF-I receptors (IGF-IR) are present in wide parts of the brain. GH-R immunoreactivity is found in both neurons, astrocytes and oligodendrocytes [Lobie P. E. et al., Brain Res. Dev. Brain Res. 1993, 74:225-233]. Abundant GH-R expression is found in the choroid plexus. IGF-I-R is expressed in neuronal stem cells [Aberg M. A. et al., Mol. Cell. Neurosci. 2003, 24:23-40] but also present in neurons and glial cells throughout the brain [Chung Y. H. et al., Brain Res. 2002, 946:307-313].
The choroid plexus, which is a key area of the blood-brain-barrier (BBB), has abundance of GH-R and IGF-I-R as shown in both ligand-binding experiments [Araujo D. M. et al., Brain Res. 1989, 484:130-138] and from IGF-I-R mRNA studies [Aguado F. et al., J. Mol. Endocrinol. 1993, 11: 231-239]. Apart from GH and IGF-I in the circulation there is a local synthesis of both GH and IGF-I in the brain outside the pituitary. IGF-I immunoreactivity is also widespread in all types of neurons in the brain [D'Ercole A. J. et al., Mol. Neurobiol. 1996, 13:227-255]. IGF-I expression in the CNS is particularly high during fetal development and peaks during the first 2 postpartum weeks, predominantly in neurons but also in glial progenitors [Bach M. A. et al., Brain Res. Mol. Brain Res. 1991, 10:43-48; Bartlett W. P., Brain Res. Mol. Brain Res. 1992, 12:285-291].
GH is taken up from the bloodstream into the brain parenchyma. GH-R is present in the choroid plexus which plays a role in the transport of GH across the BBB [Lai Z. N. et al., Brain Res. 1991, 546:222-226]. When GH was administered peripherally to patients with GH deficiency, a tenfold increase in GH in the cerebrospinal fluid was reported [Johansson J. O. et al., Neuroendocrinology 1995, 61:57-66].
It appears that IGF-I uptake is mediated by a specific carrier both in the capillary bed in the BBB [Duffy K R, Pardridge W M, Rosenfeld R G. Human blood-brain barrier insulin-like growth factor receptor. Metabolism 1988; 37:136-140] and in the blood-CSF barrier [Armstrong C. S. et al., J. Neurosci. Res. 2000, 59:649-660; Cam E. et al., J. Neurosci. 2005, 25:10884-10893].
It is important to note that local brain GH appears earlier in embryonic life than pituitary GH [Harvey S. and Hull K., J. Mol. Neurosci. 2003, 20:1-14]. In a rat model, postnatal brain development on days 6-27 following GH administration was enhanced [Diamond M. C., Brain Res. 1968, 7:407-418]. It appears that circulating GH and IGF-I has both cell proliferative and cell-survival promoting effects in the CNS [Aberg N. D. et al., Endocrinology 2007. 148:3765-3772]. IGF-I-R and estrogen-R interact in the promotion of neuronal survival and neuro-protection [Garcia-Segura L. M. et al., J. Neurocytology 2000, 29:425-437].
There are three major lines of evidence that support the notion of effects by GH/IGF-I on the human brain. First, the presence of the early GH and IGF-I system in the human brain has a similar appearance to that of rodents [Aberg N. D. et al., Scientific World J. 2006, 18; 6:53-80]. Accumulating studies show positive beneficial cognitive effects of GH substitution in GH-deficient patients [Falleti M. G. et al., Psychoneuroendocrinology 2006, 31:681-691]. With respect to neurogenesis, this phenomenon has been shown to occur in the adult human hippocampus [Eriksson P. S. et al., Nat. Med. 1998, 4:1313-1317].
Repeated testing of IQ and head circumference (HC) measurement in four children with congenital isolated growth hormone deficiency (IGHD) revealed a catch-up in both parameters in two patients treated at ages 33/12 and 45/12 but had no effect in two patients treated at ages 91/12 and 135/12 [Laron Z. and Galatzer A., Early Hum. Develop. 1981, 5:211-214]. Lagrou: et al [Lagrou K. et al., Eur. J. Endocrinol. 2007, 156:195-201] “Started hGH treatment in children at a mean age of 5.5±1.4”/2 years and found no effect. The inventors also found that initiation of hGH treatment of GHD children aged 2.9±1.4 years and a bone age of 1.2±0.9 years has faster and better effects on linear growth compared to children in whom treatment was started at a later age [Josefsberg Z. et al., Horm. Res. 1987, 27:126-133]. It should be explained that “bone age” is a way of describing the degree of maturation of the child's biological age. The “bone age” of a child is the average age at which children reach this stage of biological maturation. The inventors have also found that IGF-I treatment in Laron syndrome patients results in a fast catch-up growth of the HC [Laron Z. et al., Lancet 1992, 339:1258-1261].
The seemingly controversial effects of GH treatment on cognition [Siegel P. T. and Hopwood H. N., “The Relationship of Academic Achievement and the Intellectual Functioning and Affective Conditions of Hypopituitary Children”. Hillsdale, N.J., Erlbaum, 1986; Sandberg D. et al., Children's Health Care 1998, 27:265-282; Smith M. O. et al., J. Dev. Behay. Pediatr. 1985, 6:273-278 (1990)], probably stems from the differences in diagnosis of these groups and from the age at treatment and from the biological age (bone age) at which treatment was initiated. Although very intriguing, the effects of GH or IGF-I therapy on neurogenesis (and other cell genesis) in naïve young animals have not been studied so far. This is an area of research which is very important, as the plasticity of the CNS seems to be greater in younger individuals.
Without being bound by theory, the inventors propose that the brain and its functions undergo a time-limited maturation during a relatively short period in-utero and in early postnatal life. This period is a window in which the developmental processes seem to respond to external factors. Thus, by early administration of GH to SGA patients under the age of two years, specifically, between about six-months to two years, the invention provides prevention of future neurological and psychological damage.
It is therefore an object of the invention to provide prophylactic methods for the treatment of small-for-gestational-age (SGA)-associated disorders, specifically, conditions associated with neurological damage, using growth hormone (GH) or any compound that increases blood levels of at least one of hGH and IGF-I, applied to SGA infants under two years of age.
In yet another object, the invention provides the use of GH for preventing SGA-associated disorders, specifically, conditions associated with neurological damage, in SGA infants under two years of age.
These and other objects of the invention will become apparent by the hand of the following description.